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Lung cancer results in the largest number of cancer- and tumour microenvironment studies might be used
related deaths worldwide1,2. More than 85% of those to improve the survival of patients with NSCLC through
cases are currently classified as non-small-cell lung the development of novel therapeutic strategies.
cancer (NSCLC), for which the predicted 5‑year sur-
vival rate is 15.9% — a figure that has only marginally Defining NSCLC subsets
improved during the past few decades3. Technological NSCLC is currently defined by pathological character
1
Department of Medical
Oncology, Dana-Farber advances during the past decade, including the intro- istics. The two predominant NSCLC histological pheno-
Cancer Institute, Boston, duction of next-generation sequencing (NGS), the types are adenocarcinoma (ADC; ~50%) and squamous
Massachusetts 02115, USA. generation of multiple genetically engineered mouse cell carcinoma (SCC; ~40%)4,5. In general, ADCs arise in
2
Stem Cell Program, Boston models (GEMMs) of lung cancer and the construction more distal airways, whereas SCCs arise in more proxi-
Children’s Hospital, Boston,
Massachusetts 02115, USA.
of large databases characterizing the molecular fea- mal airways and are more strongly associated with smok-
3
Harvard Stem Cell Institute, tures of human tumours, have transformed our view of ing and chronic inflammation than ADCs4,5. ADCs often
Cambridge, Massachusetts NSCLC from histopathological descriptions to precise have glandular histology and express biomarkers that
02138, USA. molecular and genetic identities that can be resolved to are consistent with an origin in the distal lung, includ-
4
Department of Genetics,
the single-cell level. In parallel, approaches and concepts ing thyroid transcription factor 1 (TTF1; also known
Harvard Medical School,
Boston, Massachusetts from fields such as developmental biology, stem cell biol- as NKX2‑1) and keratin 7 (KRT7)4,5. By contrast, SCCs
02115, USA. ogy and immunology have deepened our knowledge of are characterized by squamous differentiation, which is
5
Department of Medicine, tumour development, cellular heterogeneity and inter- more reminiscent of the pseudostratified columnar epi-
Harvard Medical School, actions between the lung tumour and its surrounding thelium that lines the trachea and upper airways4,6. SCCs
Boston, Massachusetts
02115, USA.
microenvironment. These multidisciplinary efforts are distinguished from ADCs in the clinic by immuno
6
Belfer Institute for Applied have enhanced our understanding of molecular disease staining for cytokeratin 5 and cytokeratin 6 and/or
Cancer Science, Dana-Farber mechanisms, thereby forming the rationales for target- the transcription factors SRY-box 2 (SOX2) and p63
Cancer Institute, Boston, ing different cellular compartments simultaneously. (REFS 4,5,7). Other subtypes of NSCLC include large cell
Massachusetts 02115, USA.
Scientists and physicians have better tools than ever to carcinoma, which is diagnosed by exclusion if tumour
*These authors contributed
equally to this work. pursue answers to two provocative questions: first, how cells do not appear glandular or squamous in shape or
Correspondence to P.S.H., can we define the specific subsets of NSCLC that differ express ADC or SCC biomarkers, although it is unclear
C.F.K. and K.-K.W. by cellular and molecular composition? Second, how whether large cell carcinomas are genetically distinct
e‑mails: phammerman@ can we effectively control lung cancer growth for each from ADC or SCC4. Some neuroendocrine tumours
partners.org; carla.kim@
childrens.harvard.edu;
specific subset of NSCLC? In this Review, we discuss are also classified as NSCLC, although the most aggres-
kwong1@partners.org how data that are derived from technological advances sive form of neuroendocrine tumour is classified as
doi:10.1038/nrc3775 in lung cancer genomics, mouse modelling of cancers small-cell lung cancer (SCLC)4.
Genetic mutations and genomic heterogeneity. the net effects of genotype and therapy response may be
Although histological features and marker expression achieved and will ultimately inform the most suitable
remain the basis of clinical tumour diagnosis, recent treatment strategies.
advances in NGS and other high-throughput genomic Other novel technologies have also facilitated the
profiling platforms have allowed researchers to exam- discovery and validation of somatic mutations in lung
ine the breadth of genetic mutations within lung cancer. For example, high-throughput screens using
tumours. Following the identification of KRAS and established short hairpin RNA (shRNA) libraries have
BRAF mutations8,9, epidermal growth factor receptor identified genes that cause synthetic lethality with
(EGFR) mutations were discovered in patients with common oncogenic events, such as KRAS-activating
lung ADC and were associated with response to EGFR mutations or p53 inactivation, leading to potential
inhibitors10–13. Further recurrent mutations and ampli- new treatment targets, such as TANK-binding kinase 1
fications in many potentially targetable oncogenes have (TBK1)32. Similarly, the application of mass spectro
since been identified in lung ADC, including HER2 metry to metabolomic, proteomic and phosphoki-
(also known as ERBB2), MET, fibroblast growth fac- nase profiling, as well as single cell time-of-flight mass
tor receptor 1 (FGFR1) and FGFR2, as well as fusion cytometry (cyTOF), have led to numerous new findings,
oncogenes involving anaplastic lymphoma kinase including the discovery of recurrent aberrations such as
(ALK), the ROS1 receptor tyrosine kinase, neuregu- the ROS1 fusions and the potential diagnostic or prog-
lin 1 (NRG1), neurotrophic tyrosine kinase recep- nostic marker isocitrate dehydrogenase 1 (IDH1)17,33,34.
tor type 1 (NTRK1) and RET 14–22. These oncogenic Such advances in high-throughput technology are pro-
changes, many of which predict sensitivity to clini- moting rapid advances in our understanding of NSCLC
cal inhibitors, jointly account for most cases of lung biology and, ultimately, will help to determine how
ADC23–25. For lung SCC, the number of tumours for NSCLC develops, spreads and can be better treated.
which whole-exome sequencing is available is lower
than for ADC but, so far, potentially targetable muta- Heterogeneity in lung tumour microenvironments.
tions in ADC do not seem to be prevalent in this The concept of tumour heterogeneity applies not only
histological subtype20. Instead, genes such as discoi- to tumour epithelial cells but also to the diverse micro-
din domain-containing receptor 2 (DDR2), FGFR1, environments with which the tumour cells interact 35.
FGFR2, FGFR3 and genes in the PI3K pathway seem Carcinoma cells, in the lung and other organs, are closely
to be more commonly mutated in lung SCC20. Many associated with the extracellular matrix (ECM), mesen-
of these mutations (with the exception of those in chymal cells such as fibroblasts, infiltrating immune cells
the PI3K pathway) have been validated by preclinical and vasculature (FIG. 1). In some cases, this environment
studies as driver mutations22,26,27. is essential to tumour initiation or tumour growth,
NGS studies have also revealed the molecular tax- whereas in other cases it can prevent tumorigenesis or
onomy of lung cancer and have shown a dazzling com- even promote tumour clearance35,36.
plexity of somatic alterations in NSCLCs that extends In lung tumorigenesis, genesis of new blood and lym-
far beyond protein kinases to include epigenome phatic vessels supplies necessary nutrients for tumour
modifiers, transcription factors, splicing factors and growth and allows for an influx of immune cells of the
genes involved in cellular immunity 20,28,29. Potentially myeloid and lymphoid lineages. The myeloid cells that
important mutations and copy number gains identified are implicated in this process include tumour-associated
from patient tumours are summarized in TABLE 1, with macrophages (TAMs) and tumour-associated neutro-
relevant preclinical and clinical evidence. Among the phils37. Mice that harboured germline knock‑in of kinase-
21 different tumour types for which exome sequences dead inhibitor of nuclear factor-κB (NF‑κB) kinase
were directly compared, lung SCC and ADC ranked subunit-α (IKKα) developed spontaneous lung SCC
second and third highest in median somatic muta- that is characterized by NF‑κB activation and marked
tion frequency, with an average of ten mutations per accumulation of TAMs that were essential for disease
megabase of coding DNA sequenced30. It is worth progression38. Secretion of pro-angiogenic factors such
noting that ADCs in non-smokers have 5–6‑times as platelet-derived growth factor (PDGF) and vascular
fewer mutations24,31. Given this relatively large num- endothelial growth factor (VEGF) by TAMs in lung can-
ber of mutations per tumour, there will probably be cer suggests why these cells are associated with increased
more important mutations identified for NSCLC as microvessel formation39,40. Likewise, increased neutro-
the number of tumours that are analysed increases. phil numbers have been associated with poor prognosis
An important challenge that remains is understanding in NSCLCs, perhaps owing to their ability to degrade
which of these many mutations are important in lung matrices with elastase41,42. Neutrophils that are found
Myeloid-derived
carcinogenesis and/or treatment response, in contrast in mouse tumours are phenotypically characterized as
suppressor cells
(MDSCs). MDSCs encompass a to those mutations that are merely a consequence of polymorphonuclear CD11B- and lymphocyte antigen
heterogeneous population of the tumorigenic process. Thus, the genomic profiles 6G‑expressing (CD11B+Ly6G+) cells, and are often con-
myeloid cells, which share the highlight the heterogeneity of the NSCLC genome and sidered to be a subtype of myeloid-derived suppressor cells
ability to suppress T cells provide a plausible explanation for the highly hetero- (MDSCs)43. In the tumour microenvironment, accu-
through the production of
arginase and the expression
geneous treatment responses that we have observed in mulated MDSCs are thought to promote tumour pro-
of inducible nitric oxide the clinic. By cataloguing a large collection of muta- gression by increasing matrix degradation, tumour cell
synthase (iNOS). tions for each patient, a more accurate evaluation of proliferation, metastasis and angiogenesis35,37.
Figure 2 | A diagram of proximal and distal lung cells, indicating markers that are retained in carcinomas and
putative squamous cell carcinoma (SCC) and adenocarcinoma (ADC) cells of origin. DiverseNature Reviews | Cancer
lung stem or progenitor
cell populations are thought to have the ability to drive lung oncogenesis in different contexts. In the proximal lung, the
tracheal basal cell has been proposed to be the cell of origin for lung SCC. The evidence for this relationship includes
the expression of p63, SRY-box 2 (SOX2) and keratin 5 (KRT5) within the basal cells, squamous metaplasia of the basal cells
(common in smokers), and squamous cell carcinomas. Squamous tumours are modelled in mice by KrasG12D expression and
liver kinase B1 (Lkb1) knockout (20% of lesions are squamous), knocking in a germline dominant-negative kinase-dead
inhibitor of nuclear factor-κB kinase subunit-α (IKKα) and knocking out both Lkb1 and Pten (100% of lesions are squamous
for the second two models). Two bronchiolar cell populations, the bronchiolar progenitor cells and the bronchioalveolar
stem cells (BASCs) may also be able to give rise to tumours with squamous characteristics, although experimental lineage
tracing is needed to confirm this theory. ADCs can be modelled by KrasG12D expression (long latency), KrasG12D expression
and Trp53‑null, and epidermal growth factor receptor (EGFR)T790M/L858R, among other genetic models, and they are thought
to arise from more proximal airway cells. These tumours often retain characteristics of proximal airways, such as the
expression of surfactant protein C (SPC), KRT7 and thyroid transcription factor 1 (TTF1). Again, BASCs or bronchiolar
progenitor cells, which are able to give rise to alveolar lineages after lung injury, may likewise be able to give rise to
tumours with alveolar characteristics. AcTUB, acetylated tubulin; AT, alveolar epithelial type; CCSP, club cell secretory
protein; CGRP, calcitonin gene-related peptide.
club cells and BASCs produces lung tumours that express transplantation assays. Establishment of tumours at
the marker p63 but histologically resemble ADCs7. This metastatic sites and tumour recurrence following treat-
intriguing finding suggests that distal lung epithelia are ment have been attributed to growth and survival of
unable to produce a fully squamous phenotype, despite the TPCs67,68. Recent studies have identified potential cell
expression of an SCC transcription factor. In addition, surface markers or genetic traits that may mark the TPC
the deletion of Lkb1 and Pten in the lung via intranasal population in NSCLC, such as aldehyde dehydroge-
adenovirus-Cre was recently shown to give rise to fully nase (ALDH) activity or expression of NOTCH, CD24,
penetrant lung SCCs49. The next important step will be to CD166 or CD44 (REFS 38,69–73). However, these stud-
use lineage-restricted Cre alleles, such as the oestrogen- ies have not used serial transplant assays in the context
responsive Cre under control of the Krt5 promoter of the lung environment, and a bona fide human lung
(Krt5–Cre-ER), to determine which lung cells that are TPC remains to be defined. GEMMs have allowed for
null for Lkb1 and Pten are able to drive squamous disease. more systematic study of lung TPC phenotypes, includ-
ing serially transplanted tumours and metastases. Studies
Tumour-propagating cells (TPCs) and cellular plastic- in the KrasG12D-expressing and Trp53‑null model of ADC
ity: heterogeneity between tumour cells. ‘Cancer stem suggest that stem cell antigen 1 (SCA1, also known as
cells’ or TPCs, which are defined as the tumour cells Ly6A)+, CD24+, β4 integrin+, and NOTCH3hi mark
with the stem cell-properties of self-renewal and dif- the TPC population70,73. The identity of TPCs from
ferentiation, have the capacity to produce tumours in other ADC GEMMs is unknown; SCA1 did not enrich
Cytotoxic T lymphocyte clear challenges to our current ideas about treatment enable marked perturbation of gene expression within
protein 4 approaches — in cases in which there is no clear drugga- tumour cells to stop tumour growth. The recently devel-
(CTLA4; also known as ble target, what can be done? Furthermore, the short-lived oped bromodomain protein inhibitors have shown effi-
CD152). A surface receptor in vivo efficacy for most if not all existing small molecule cacy in numerous preclinical studies116, including in lung
that transmits inhibitory
signals to T cells.
inhibitors87,106 also advocates more durable treatment cancer 117, and they are currently under evaluation in the
approaches. On the basis of our current understanding, clinic, including in the ongoing Phase I clinical trials
CD73 the more effective approach probably requires therapies NCT01987362 and NCT01587703. Variations in expres-
A cell surface enzyme that that not only target tumour cells but also target other sion as well as recurrent mutations were also reported
generates extracellular
components of the tumour, such as tumour vasculature, for several histone- and DNA-modifying enzymes,
adenosine, which inhibits
T cell function.
tumour-associated fibroblasts and tumour-specific and/or including enhancer of zeste homologue 2 (EZH2), TET
non-specific immune cells. Besides the more recently methylcytosine dioxygenase 2 (TET2) and DNA methyl
CD47 studied PD1–PDL1 inhibitory pathway, other approaches transferase 3A (DNMT3A) in all subtypes of NSCLC28.
The receptor for that intervene with the immune system, such as antibod- In a similar concept, altered metabolism is one of the key
thrombospondin 1 (TSP1).
CD47 is highly expressed in
ies against cytotoxic T lymphocyte protein 4 (CTLA4; also features of cancer cells. Anti-diabetic drugs, insulin-like
many tumour cells. known as CD152), CD73 or CD47, and more sophisticated growth factor 1 receptor (IGF1R) inhibitors and drugs
cellular immune therapies, such as engineered T cell that target glycolysis or lipid, nucleic acid and amino acid
Chimeric antigen receptors therapy using chimeric antigen receptors (CARs), are also synthesis are currently being explored for antitumour
(CARs). Genetically engineered
under extensive scrutiny 107–110. More importantly, ongo- activities in NSCLC118–121. Targeting metabolism is cer-
receptors that result in desired
specificity (to tumour cells) in
ing efforts are seeking to discover the best combination tainly promising for cancer control, particularly when
effector T cells. approach that integrates immune therapy with other combined with other approaches. Recent studies have also
therapies. Angiogenesis has long been seen as a possible highlighted connections between TET and IDH, which
CpG island methylator therapeutic window, with many novel therapeutic agents could have resulted in a CpG island methylator phenotype
phenotype
(CIMP). Reflects the genomic
that have been developed or are being developed to clini- (CIMP) in a subset of lung cancer, and this ‘connects the
status that multiple CpG cally target this process, although the overall efficacy of dots’ between epigenetics and metabolism122–124.
islands are methylated anti-angiogenic agents has been modest in unselected
simultaneously, leading to patient cohorts111. Emerging evidence has suggested that Conclusion
epigenetic inactivation of
the combination of immunotherapy and anti-angiogenic The quickened pace of discovery of mechanisms that
different genes, including
tumour suppressors.
agents has potential synergistic effects112,113, pointing to underlie lung cancer development and possible treatments
a new possible avenue to mutually enhance both treat- in the past decade present the opportunity to integrate
ments. In addition to providing key nutrients and oxy- information from multiple approaches for future lung
genated blood, tumour vasculature might have a role cancer treatment. Large amounts of information about the
in supporting TPCs35,114. Similarly, stromal cells such as identity of individual lung tumours are being collected.
fibroblasts have been shown to provide additional signals New and improved functional studies are needed to meet
that support tumour growth and survival, and they may the pace of data set generation, and all of the aspects of
therefore have major roles in primary and acquired treat- tumour heterogeneity — genetic, cellular and epigenetic
ment resistance35,115. Understanding how best to target — need to be integrated to determine better approaches to
these various aspects of the tumour microenvironment make an impact in this devastating disease. We anticipate
would require a high-throughput comparison of changes the future treatment scheme to be a genotype-depend-
in the tumour microenvironment that occur upon single ent, carefully selected combination that would ensure an
and combination treatments. enhanced tumour immune reaction, inhibition of angio-
Targeted therapies might also be able to indirectly genesis and blockade of interactions between tumour cells
regulate tumour growth. Two prominent examples are and stromal cells. Thus, we advocate ‘integrated therapy’,
drugs that target epigenetic enzymes and metabolic in contrast to the current concept of targeted therapy, as
enzymes. Targeting epigenetic enzymes is expected to the future of effective NSCLC treatment.
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